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1
Klimov, E. A., A. V. Malakhova, L. A. Korobeinikova, et al. "Polymorphic variants of the cholecystokinergic system genes: associations with panic disorders." Medical Council, no. 12 (July 29, 2018): 190–94. http://dx.doi.org/10.21518/2079-701x-2018-12-190-194.
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Panic disorder is a widespread socially significant disease, which genetic nature is extremely poorly known. The gene of this neuropeptide (CCK) and its receptors (CCKAR, CCK2R) have being actively studied since the discovery of panicogenic properties of cholecystokinin. The purpose of this work was to estimate the degree of incidence of seven single nucleotide substitutions in the CCK, CCKAR and CCKBR genes in the population of patients diagnosed with panic disorder and a control population consisting of unexamined residents of the Moscow region. A significant increase in the degree of incidence of the T allele of the single nucleotide substitution 109C/T (rs1805000) in the CCKBR gene was identified in the patient population as compared with the controls, prompting suggestions that this substitution is involved in the aetiology of panic disorder. It also demonstrated the association of the combination of alleles -36T CCK, -128T CCKAR (rs11571842 and rs1800908, respectively) with the development of a panic disorder.
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Chandra, Abhijit, Jaya Nigam, Madhumati Goel, Devendra Parmar, and Leena Khare Satyam. "Expression and heterodimerization of Type A and B Cholecystokinin Receptors in Gallbladder cancer." Journal of Clinical Oncology 37, no. 15_suppl (2019): e15655-e15655. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15655.
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e15655 Background: Gallbladder cancer is the most common malignancy of the biliary tract and endemic in Northern India. The prognosis of gallbladder cancer remains dismal despite any treatment because of late presentation and aggressive tumor biology. Cholecystokinin (CCK) is present in abundance in gallbladder tissue and mediates function through two structurally related receptors, the type A (CCKAR) and B (CCKBR) receptors. Previously, heterodimerization of CCKAR and CCKBR receptor has been demonstrated in vitro, and was shown to bind natural agonists normally but exhibited agonist stimulated cellular signaling, promoting cell growth. In this study we examined the expression level of CCKAR and CCKBR in resected gallbladder tissue samples and also attempted to determine the dimerization status of CCKAR and CCKBR receptors in gallbladder cancer comparing them to cholelithiasis and normal gallbladder tissue. Methods: Tissue samples from resected normal gallbladder (n = 10), cholelithiasis (n = 25) and gallbladder cancer (n = 25)) were evaluated for the expression of CCKAR and CCKBR by immunohistochemistry. Determination of CCKAR and CCKBR expression was also done by western blot in representative samples from each of these tissue types while their dimerization status was evaluated by immunoprecipitation. Results: By Immunohistochemistry technique, positive CCKAR expression was observed in 80% gallbladder cancer, 84% cholelithiasis, 90% normal gallbladder, P = 0.76. However significantly higher expression of CCKBR was noted in gallbladder cancer (60%) as compared to cholelithiasis (25%) and normal gallbladder (20%), P = 0.013. We also observed progressively increasing level of expression of CCKAR and CCKBR in gallbladder cancer as compared to cholelithiasis and normal gallbladder by western blot. In addition, we also observed a higher level of heterodimer formation in gallbladder cancer compared to cholelithiasis and normal gallbladder using immunoprecipitation technique. Conclusions: Our results provide the first evidence of increasing trend of heterodimerization of CCKAR and CCKBR in gallbladder cancer which has potential clinical and therapeutic significance.
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Norden-Krichmar, Trina M., Ian R. Gizer, Evelyn Phillips, Kirk C. Wilhelmsen, Nicholas J. Schork, and Cindy L. Ehlers. "Variants Near CCK Receptors are Associated With Electrophysiological Responses to Pre-pulse Startle Stimuli in a Mexican American Cohort." Twin Research and Human Genetics 18, no. 6 (2015): 727–37. http://dx.doi.org/10.1017/thg.2015.77.
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Neurophysiological measurements of the response to pre-pulse and startle stimuli have been suggested to represent an important endophenotype for both substance dependence and other select psychiatric disorders. We have previously shown, in young adult Mexican Americans (MA), that presentation of a short delay acoustic pre-pulse, prior to the startle stimuli can elicit a late negative component at about 400 msec (N4S), in the event-related potential (ERP), recorded from frontal cortical areas. In the present study, we investigated whether genetic factors associated with this endophenotype could be identified. The study included 420 (age 18–30 years) MA men (n = 170), and women (n = 250). DNA was genotyped using an Affymetrix Axiom Exome1A chip. An association analysis revealed that the CCKAR and CCKBR (cholecystokinin A and B receptor) genes each had a nearby variant that showed suggestive significance with the amplitude of the N4S component to pre-pulse stimuli. The neurotransmitter cholecystokinin (CCK), along with its receptors, CCKAR and CCKBR, have been previously associated with psychiatric disorders, suggesting that variants near these genes may play a role in the pre-pulse/startle response in this cohort.
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Kazmi, Hasan Raza, Abhijit Chandra, Kavita Baghel, et al. "Differential Expression of Cholecystokinin A Receptor in Gallbladder Cancer in the Young and Elderly Suggests Two Subsets of the Same Disease?" BioMed Research International 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/625695.
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Background. Cholecystokinin type A receptor (CCKAR) is known to be overexpressed in variety of human malignancies but information regarding its expression in gallbladder cancer (GBC) is limited. Attempts were now made to investigate expression pattern of CCKAR mRNA and protein in controls and GBC patients and correlate it with various clinicopathological parameters following surgical resection.Materials and Methods. Gallbladder tissue samples from 64 subjects (GBC: 39; control: 25) were studied. Expression of CCKAR mRNA was evaluated by reverse transcriptase-polymerase chain reaction and confirmed using real-time polymerase chain reaction. Protein expression was studied by enzyme-linked immunosorbent assay.Results. Significantly higher expression of CCKAR mRNA(P<0.0001)and protein(P<0.0001)was observed in GBC tissues. Overexpression was also observed for stage III and in moderately and poorly differentiated tumors. When the clinicopathological parameters were compared, we found age dependent decrease in CCKAR expression. Relatively higher expression of CCKAR was observed in younger patients (age < 45 years) having more aggressive disease when compared with elderly ones (age ≥ 45 years).Conclusions. Age related differential expression of CCKAR in GBC may suggest two possible variants of the disease in this endemic belt.
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Takiguchi, Soichi, Yutaka Takata, Nobuhiko Takahashi, et al. "A disrupted cholecystokinin A receptor gene induces diabetes in obese rats synergistically with ODB1 gene." American Journal of Physiology-Endocrinology and Metabolism 274, no. 2 (1998): E265—E270. http://dx.doi.org/10.1152/ajpendo.1998.274.2.e265.
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Otsuka Long-Evans Tokushima fatty (OLETF) rats develop hyperglycemia, hyperinsulinemia, and mild obesity, which are characteristic of human non-insulin-dependent diabetes mellitus. We have shown that two recessive genes, ODB1 mapped on the X chromosome and ODB2 mapped on chromosome 14, are involved in the induction of the diabetes in OLETF rats. Recently we found that OLETF rats are the naturally occurring cholecystokinin type A receptor (CCKAR) gene knockout rats. In this study, we focused on the genotype of CCKAR gene and the ODB1 gene in regulation of glucose homeostasis in the F2 cross of the OLETF rats. Relatively high plasma glucose levels were observed in the F2 offspring with the homozygously disrupted CCKAR gene. A synergistic effect for increasing plasma glucose levels in F2 rats between disrupted CCKAR gene and the ODB1 gene was shown. The CCKAR gene was found to map very close to ODB2 by a linkage analysis using microsatellite markers. These results suggest that CCKAR gene maintains normoglycemia in rats.
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Wang, Helen H., Piero Portincasa, Min Liu, Patrick Tso, and David Q. H. Wang. "An Update on the Lithogenic Mechanisms of Cholecystokinin a Receptor (CCKAR), an Important Gallstone Gene for Lith13." Genes 11, no. 12 (2020): 1438. http://dx.doi.org/10.3390/genes11121438.
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The cholecystokinin A receptor (CCKAR) is expressed predominantly in the gallbladder and small intestine in the digestive system, where it is responsible for CCK’s regulation of gallbladder and small intestinal motility. The effect of CCKAR on small intestinal transit is a physiological response for regulating intestinal cholesterol absorption. The CCKAR gene has been identified to be an important gallstone gene, Lith13, in inbred mice by a powerful quantitative trait locus analysis. Knockout of the CCKAR gene in mice enhances cholesterol cholelithogenesis by impairing gallbladder contraction and emptying, promoting cholesterol crystallization and crystal growth, and increasing intestinal cholesterol absorption. Clinical and epidemiological studies have demonstrated that several variants in the CCKAR gene are associated with increased prevalence of cholesterol cholelithiasis in humans. Dysfunctional gallbladder emptying in response to exogenously administered CCK-8 is often found in patients with cholesterol gallstones, and patients with pigment gallstones display an intermediate degree of gallbladder motility defect. Gallbladder hypomotility is also revealed in some subjects without gallstones under several conditions: pregnancy, total parenteral nutrition, celiac disease, oral contraceptives and conjugated estrogens, obesity, diabetes, the metabolic syndrome, and administration of CCKAR antagonists. The physical–chemical, genetic, and molecular studies of Lith13 show that dysfunctional CCKAR enhances susceptibility to cholesterol gallstones through two primary mechanisms: impaired gallbladder emptying is a key risk factor for the development of gallbladder hypomotility, biliary sludge (the precursor of gallstones), and microlithiasis, as well as delayed small intestinal transit augments cholesterol absorption as a major source for the hepatic hypersecretion of biliary cholesterol and for the accumulation of excess cholesterol in the gallbladder wall that further worsens impaired gallbladder motor function. If these two defects in the gallbladder and small intestine could be prevented by the potent CCKAR agonists, the risk of developing cholesterol gallstones could be dramatically reduced.
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Li, Ying, Xiaoyin Wu, Shiyi Zhou, and Chung Owyang. "Low-affinity CCK-A receptors are coexpressed with leptin receptors in rat nodose ganglia: implications for leptin as a regulator of short-term satiety." American Journal of Physiology-Gastrointestinal and Liver Physiology 300, no. 2 (2011): G217—G227. http://dx.doi.org/10.1152/ajpgi.00356.2010.
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The paradigm for the control of feeding behavior has changed significantly. Research has shown that leptin, in the presence of CCK, may mediate the control of short-term food intake. This interaction between CCK and leptin occurs at the vagus nerve. In the present study, we aimed to characterize the interaction between CCK and leptin in the vagal primary afferent neurons. Single neuronal discharges of vagal primary afferent neurons innervating the gastrointestinal tract were recorded from rat nodose ganglia. Three groups of nodose ganglia neurons were identified: group 1 responded to CCK-8 but not leptin; group 2 responded to leptin but not CCK-8; group 3 responded to high-dose CCK-8 and leptin. In fact, the neurons in group 3 showed CCK-8 and leptin potentiation, and they responded to gastric distention. To identify the CCK-A receptor (CCKAR) affinity states that colocalize with the leptin receptor OB-Rb, we used CCK-JMV-180, a high-affinity CCKAR agonist and low-affinity CCKAR antagonist. As expected, immunohistochemical studies showed that CCK-8 administration significantly potentiated the increase in the number of c-Fos-positive neurons stimulated by leptin in vagal nodose ganglia. Administration of CCK-JMV-180 eliminated the synergistic interaction between CCK-8 and leptin. We conclude that both low- and high-affinity CCKAR are expressed in nodose ganglia. Many nodose neurons bearing low-affinity CCKAR express OB-Rb. These neurons also respond to mechanical distention. An interaction between CCKAR and OB-Rb in these neurons likely facilitates leptin mediation of short-term satiety.
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Nishimura, Sayoko, Kaya Bilgüvar, Keiko Ishigame, Nenad Sestan, Murat Günel, and Angeliki Louvi. "Functional Synergy between Cholecystokinin Receptors CCKAR and CCKBR in Mammalian Brain Development." PLOS ONE 10, no. 4 (2015): e0124295. http://dx.doi.org/10.1371/journal.pone.0124295.
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Okubo, T., and S. Harada. "Polymorphisms of the CCK, CCKAR and CCKBR genes: an association with alcoholism study." Journal of Studies on Alcohol 62, no. 4 (2001): 413–21. http://dx.doi.org/10.15288/jsa.2001.62.413.
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Reidelberger, Roger D., Dean Heimann, Linda Kelsey, and Martin Hulce. "Effects of peripheral CCK receptor blockade on feeding responses to duodenal nutrient infusions in rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 284, no. 2 (2003): R389—R398. http://dx.doi.org/10.1152/ajpregu.00529.2002.
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Type A cholecystokinin receptor (CCKAR) antagonists differing in blood-brain barrier permeability were used to test the hypothesis that duodenal delivery of protein, carbohydrate, and fat produces satiety in part by an essential CCK action at CCKARs located peripheral to the blood-brain barrier. Fasted rats with open gastric fistulas received devazepide (1 mg/kg iv) or A-70104 (700 nmol · kg−1· h−1iv) and either a 30-min intravenous infusion of CCK-8 (10 nmol · kg−1· h−1) or duodenal infusion of peptone, maltose, or Intralipid beginning 10 min before 30-min access to 15% sucrose. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of Nα-3-quinolinoyl-d-Glu- N,N-dipentylamide, does not. CCK-8 inhibited sham feeding by ∼50%, and both A-70104 and devazepide abolished this response. Duodenal infusion of each of the macronutrients dose dependently inhibited sham feeding. A-70104 and devazepide attenuated inhibitory responses to each macronutrient. Thus endogenous CCK appears to act in part at CCKARs peripheral to the blood-brain barrier to inhibit food intake.
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Reidelberger, Roger D., Daniel A. Castellanos, and Martin Hulce. "Effects of peripheral CCK receptor blockade on food intake in rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 285, no. 2 (2003): R429—R437. http://dx.doi.org/10.1152/ajpregu.00176.2003.
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Type A cholecystokinin receptor (CCKAR) antagonists differing in blood-brain barrier permeability were used to test the hypothesis that satiety is mediated, in part, by CCK action at CCKARs located peripheral to the blood-brain barrier. At dark onset, non-food-deprived rats received a bolus injection of devazepide (2.5 μmol/kg iv), a 3-h infusion of A-70104 (1 or 3 μmol·kg-1·h-1 iv), or vehicle either alone or coadministered with a 3-h infusion of CCK-8 (10 nmol·kg-1·h-1 iv) or a 2-h intragastric infusion of peptone (1 g/h). Food intake was determined from continuous computer recordings of changes in food bowl weight. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of Nα-3-quinolinoyl-d-Glu- N,N-dipentylamide (A-65186), does not. CCK-8 inhibited 3-h food intake by more than 50% and both A-70104 and devazepide abolished this response. A-70104 and devazepide stimulated food intake and similarly attenuated the anorexic response to intragastric infusion of peptone. Thus endogenous CCK appears to act, in part, at CCKARs peripheral to the blood-brain barrier to inhibit food intake.
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Reidelberger, Roger D., Linda Kelsey, Dean Heimann, and Martin Hulce. "Effects of peripheral CCK receptor blockade on gastric emptying in rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 284, no. 1 (2003): R66—R75. http://dx.doi.org/10.1152/ajpregu.00484.2002.
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Type A CCK receptor (CCKAR) antagonists differing in blood-brain barrier permeability [devazepide penetrates; the dicyclohexylammonium salt of Nα-3-quinolinoyl-d-Glu- N,N-dipentylamide (A-70104) does not] were used to test the hypothesis that duodenal nutrient-induced inhibition of gastric emptying is mediated by CCKARs located peripheral to the blood-brain barrier. Rats received A-70104 (700 or 3,000 nmol · kg−1· h−1iv) or devazepide (2.5 μmol/kg iv) and either a 15-min intravenous infusion of CCK-8 (3 nmol · kg−1· h−1) or duodenal infusion of casein, peptone, Intralipid, or maltose. Gastric emptying of saline was measured during the last 5 min of each infusion. A-70104 and devazepide abolished the gastric emptying response to a maximal inhibitory dose of CCK-8. Each of the macronutrients inhibited gastric emptying. A-70104 and devazepide attenuated inhibitory responses to each macronutrient. Intravenous injection of a CCK antibody to immunoneutralize circulating CCK had no effect on peptone or Intralipid-induced responses. Thus endogenous CCK appears to act in part by a paracrine or neurocrine mechanism at CCKARs peripheral to the blood-brain barrier to inhibit gastric emptying.
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Taher, Shèdy, Yamilette Borja, Lucía Cabanela, et al. "Cholecystokinin, gastrin, cholecystokinin/gastrin receptors, and bitter taste receptor TAS2R14: trophoblast expression and signaling." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 316, no. 5 (2019): R628—R639. http://dx.doi.org/10.1152/ajpregu.00153.2018.
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We investigated expression of cholecystokinin (CCK) in humans and mice, and the bitter taste receptor TAS2R14 in the human placenta. Because CCK and gastrin activate the CCKBR receptor, we also explored placental gastrin expression. Finally, we investigated calcium signaling by CCK and TAS2R14. By RT-PCR, we found CCK/Cck and GAST/Gast mRNA expression in both normal human and mouse placentas, as well as in human trophoblast cell lines (TCL). Although both Cckar and – br mRNA were expressed in the mouse placenta, only CCKBR mRNA was detected in the human placenta and TCL. mRNA expression for TAS2R14 was also observed in the human placenta and TCL. Using immunohistochemistry, CCK protein was localized to the syncytiotrophoblast (ST) and extravillous trophoblast (EVT) in the human term placenta, and to trophoblast glycogen cells in mouse and human placentas. Gastrin and TAS2R14 proteins were also observed in ST and EVT of the human placenta. Both sulfated and nonsulfated CCK elicited a comparable rise in intracellular calcium in TCL, consistent with CCKBR expression. Three TAS2R14 agonists, flufenamic acid, chlorhexidine, and diphenhydramine, also evoked rises in intracellular calcium in TCL. These results establish CCK, gastrin, and their receptor(s) in both human and mouse placentas, and TAS2R14 in the human placenta. Both CCK and TAS2R14 agonists increased intracellular calcium in human TCL. Although the roles of these ligands and receptors, and their potential cross talk in normal and pathological placentas, are currently unknown, this study opens new avenues for placental research.
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Takahashi-Iwanaga, Hiromi, Shunsuke Kimura, Kohtarou Konno, Masahiko Watanabe, and Toshihiko Iwanaga. "Intrarenal signaling mediated by CCK plays a role in salt intake-induced natriuresis." American Journal of Physiology-Renal Physiology 313, no. 1 (2017): F20—F29. http://dx.doi.org/10.1152/ajprenal.00539.2016.
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The natriuretic hormone CCK exhibits its gene transcripts in total kidney extracts. To test the possibility of CCK acting as an intrarenal mediator of sodium excretion, we examined mouse kidneys by 1) an in situ hybridization technique for CCK mRNA in animals fed a normal- or a high-sodium diet; 2) immuno-electron microscopy for the CCK peptide, 3) an in situ hybridization method and immunohistochemistry for the CCK-specific receptor CCKAR; 4) confocal image analysis of receptor-mediated Ca2+ responses in isolated renal tubules; and 5) metabolic cage experiments for the measurement of urinary sodium excretion in high-salt-fed mice either treated or untreated with the CCKAR antagonist lorglumide. Results showed the CCK gene to be expressed intensely in the inner medulla and moderately in the inner stripe of the outer medulla, with the expression in the latter being enhanced by high sodium intake. Immunoreactivity for the CCK peptide was localized to the rough endoplasmic reticulum of the medullary interstitial cells in corresponding renal regions, confirming it to be a secretory protein. Gene transcripts, protein products, and the functional activity for CCKAR were consistently localized to the late proximal tubule segments (S2 and S3) in the medullary rays, and the outer stripe of the outer medulla. Lorglumide significantly diminished natriuretic responses of mice to a dietary sodium load without altering the glomerular filtration rate. These findings suggest that the medullary interstitial cells respond to body fluid expansion by CCK release for feedback regulation of the late proximal tubular reabsorption.
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Dunn, Ian C., Simone L. Meddle, Peter W. Wilson, et al. "Decreased expression of the satiety signal receptor CCKAR is responsible for increased growth and body weight during the domestication of chickens." American Journal of Physiology-Endocrinology and Metabolism 304, no. 9 (2013): E909—E921. http://dx.doi.org/10.1152/ajpendo.00580.2012.
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Animal domestication has resulted in changes in growth and size. It has been suggested that this may have involved selection for differences in appetite. Divergent growth between chickens selected for egg laying or meat production is one such example. The neurons expressing AGRP and POMC in the basal hypothalamus are important components of appetite regulation, as are the satiety feedback pathways that carry information from the intestine, including CCK and its receptor CCKAR (CCK1receptor). Using 16 generations of a cross between a fast and a relatively slow growing strain of chicken has identified a region on chromosome 4 downstream of the CCKAR gene, which is responsible for up to a 19% difference in body weight at 12 wk of age. Animals possessing the high-growth haplotype at the locus have lower expression of mRNA and immunoreactive CCKAR in the brain, intestine, and exocrine organs, which is correlated with increased levels of orexigenic AGRP in the hypothalamus. Animals with the high-growth haplotype are resistant to the anorectic effect of exogenously administered CCK, suggesting that their satiety set point has been altered. Comparison with traditional breeds shows that the high-growth haplotype has been present in the founders of modern meat-type strains and may have been selected early in domestication. This is the first dissection of the physiological consequences of a genetic locus for a quantitative trait that alters appetite and gives us an insight into the domestication of animals. This will allow elucidation of how differences in appetite occur in birds and also mammals.
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Huppi, K., D. Siwarski, J. R. Pisegna, and S. Wank. "Chromosomal localization of the gastric and brain receptors for cholecystokinin (CCKAR and CCKBR) in human and mouse." Genomics 25, no. 3 (1995): 727–29. http://dx.doi.org/10.1016/0888-7543(95)80018-h.
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Heldsinger, Andrea, Yuanxu Lu, Shi-Yi Zhou, et al. "Cocaine- and amphetamine-regulated transcript is the neurotransmitter regulating the action of cholecystokinin and leptin on short-term satiety in rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 303, no. 9 (2012): G1042—G1051. http://dx.doi.org/10.1152/ajpgi.00231.2012.
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Vagal CCK-A receptors (CCKARs) and leptin receptors (LRbs) interact synergistically to mediate short-term satiety. Cocaine- and amphetamine-regulated transcript (CART) peptide is expressed by vagal afferent neurons. We sought to demonstrate that this neurotransmitter regulates CCK and leptin actions on short-term satiety. We also examined the signal transduction pathways responsible for mediating the CART release from the nodose ganglia (NG). ELISA studies coupled with gene silencing of NG neurons by RNA interference elucidated intracellular signaling pathways responsible for CCK/leptin-stimulated CART release. Feeding studies followed by gene silencing of CART in NG established the role of CART in mediating short-term satiety. Immunohistochemistry was performed on rat NG neurons to confirm colocalization of CCKARs and LRbs; 63% of these neurons contained CART. Coadministration of CCK-8 and leptin caused a 2.2-fold increase in CART release that was inhibited by CCK-OPE, a low-affinity CCKAR antagonist. Transfection of cultured NG neurons with steroid receptor coactivator (SRC) or phosphatidylinositol 3-kinase (PI3K) small-interfering RNA (siRNA) or STAT3 lentiviral short hairpin RNA inhibited CCK/leptin-stimulated CART release. Silencing the expression of the EGR-1 gene inhibited the CCK/leptin-stimulated CART release but had no effect on CCK/leptin-stimulated neuronal firing. Electroporation of NG with CART siRNA inhibited CCK/leptin stimulated c-Fos expression in rat hypothalamus. Feeding studies following electroporation of the NG with CART or STAT3 siRNA abolished the effects of CCK/leptin on short-term satiety. We conclude that the synergistic interaction of low-affinity vagal CCKARs and LRbs mediates CART release from the NG, and CART is the principal neurotransmitter mediating short-term satiety. CART release from the NG involves interaction between CCK/SRC/PI3K cascades and leptin/JAK2/PI3K/STAT3 signaling pathways.
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Takiguchi, Soichi, Yutaka Takata, Akihiro Funakoshi, et al. "Disrupted cholecystokinin type-A receptor (CCKAR) gene in OLETF rats." Gene 197, no. 1-2 (1997): 169–75. http://dx.doi.org/10.1016/s0378-1119(97)00259-x.
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Ocklenburg, Sebastian, Larissa Arning, Wanda M. Gerding, Jörg T. Epplen, Onur Güntürkün, and Christian Beste. "Cholecystokinin A Receptor (CCKAR) Gene Variation Is Associated with Language Lateralization." PLoS ONE 8, no. 1 (2013): e53643. http://dx.doi.org/10.1371/journal.pone.0053643.
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Okubo, Takehito, Shoji Harada, Susumu Higuchi, and Sachio Matsushita. "Investigation of Quantitative Trait Loci in the CCKAR Gene With Susceptibility to Alcoholism." Alcoholism: Clinical and Experimental Research 26, s1 (2002): 2s—5s. http://dx.doi.org/10.1111/j.1530-0277.2002.tb02693.x.
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Clutter, A. C., S. Sasaki, and D. Pomp. "Rapid communication: the cholecystokinin type-A receptor (CCKAR) gene maps to porcine chromosome 8." Journal of Animal Science 76, no. 7 (1998): 1983. http://dx.doi.org/10.2527/1998.7671983x.
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Liang, Liyang, Yingjun Xie, Yiping Shen, Qibin Yin, and Haiming Yuan. "A Rare de novo Interstitial Duplication at 4p15.2 in a Boy with Severe Congenital Heart Defects, Limb Anomalies, Hypogonadism, and Global Developmental Delay." Cytogenetic and Genome Research 150, no. 2 (2016): 112–17. http://dx.doi.org/10.1159/000454698.
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Proximal 4p deletion syndrome is a relatively rare genetic condition characterized by dysmorphic facial features, limb anomalies, minor congenital heart defects, hypogonadism, cafe-au-lait spots, developmental delay, tall and thin habitus, and intellectual disability. At present, over 20 cases of this syndrome have been published. However, duplication of the same region in proximal 4p has never been reported. Here, we describe a 2-year-5-month-old boy with severe congenital heart defects, limb anomalies, hypogonadism, distinctive facial features, pre- and postnatal developmental delay, and mild cognitive impairments. A de novo 4.5-Mb interstitial duplication at 4p15.2p15.1 was detected by chromosomal microarray analysis. Next-generation sequencing was employed and confirmed the duplication, but revealed no additional pathogenic variants. Several candidate genes in this interval responsible for the complex clinical phenotype were identified, such as RBPJ, STIM2, CCKAR, and LGI2. The results suggest a novel contiguous gene duplication syndrome.
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Sekiguchi, Toshio, Michio Ogasawara, and Honoo Satake. "Molecular and functional characterization of cionin receptors in the ascidian, Ciona intestinalis: the evolutionary origin of the vertebrate cholecystokinin/gastrin family." Journal of Endocrinology 213, no. 1 (2012): 99–106. http://dx.doi.org/10.1530/joe-11-0410.
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Cholecystokinin (CCK) and gastrin are vertebrate brain–gut peptides featured by a sulfated tyrosine residue and a C-terminally amidated tetrapeptide consensus sequence. Cionin, identified in the ascidian, Ciona intestinalis, the closest species to vertebrates, harbors two sulfated tyrosines and the CCK/gastrin consensus tetrapeptide sequence. While a putative cionin receptor, cior, was cloned, the ligand–receptor relationship between cionin and CioR remains unidentified. Here, we identify two cionin receptors, CioR1 and CioR2, which are the aforementioned putative cionin receptor and its novel paralog respectively. Phylogenetic analysis revealed that CioRs are homologous to vertebrate CCK receptors (CCKRs) and diverged from a common ancestor in the Ciona-specific lineage. Cionin activates intracellular calcium mobilization in cultured cells expressing CioR1 or CioR2. Monosulfated and nonsulfated cionin exhibited less potent or no activity, indicating that CioRs possess pharmacological features similar to the vertebrate CCK-specific receptor CCK1R, rather than its subtype CCK2R, given that a sulfated tyrosine in CCK is required for binding to CCK1R, but not to CCK2R. Collectively, the present data reveal that CioRs share a common ancestor with vertebrate CCKRs and indicate that CCK and CCK1R form the ancestral ligand–receptor pair in the vertebrate CCK/gastrin system. Cionin is expressed in the neural complex, digestive organs, oral siphon and atrial siphons, whereas the expression of ciors was detected mainly in these tissues and the ovary. Furthermore, cioninergic neurons innervate both of the siphons. These results suggest that cionin is involved in the regulation of siphonal functions.
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Desai, Aditya J., Maoqing Dong, Kaleeckal G. Harikumar, and Laurence J. Miller. "Impact of ursodeoxycholic acid on a CCK1R cholesterol-binding site may contribute to its positive effects in digestive function." American Journal of Physiology-Gastrointestinal and Liver Physiology 309, no. 5 (2015): G377—G386. http://dx.doi.org/10.1152/ajpgi.00173.2015.
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Dysfunction of the type 1 cholecystokinin (CCK) receptor (CCK1R) as a result of increased gallbladder muscularis membrane cholesterol has been implicated in the pathogenesis of cholesterol gallstones. Administration of ursodeoxycholic acid, which is structurally related to cholesterol, has been shown to have beneficial effects on gallstone formation. Our aims were to explore the possible direct effects and mechanism of action of bile acids on CCK receptor function. We studied the effects of structurally related hydrophobic chenodeoxycholic acid and hydrophilic ursodeoxycholic acid in vitro on CCK receptor function in the setting of normal and elevated membrane cholesterol. We also examined their effects on a cholesterol-insensitive CCK1R mutant (Y140A) disrupting a key site of cholesterol action. The results show that, similar to the impact of cholesterol on CCK receptors, bile acid effects were limited to CCK1R, with no effects on CCK2R. Chenodeoxycholic acid had a negative impact on CCK1R function, while ursodeoxycholic acid had no effect on CCK1R function in normal membranes but was protective against the negative impact of elevated cholesterol on this receptor. The cholesterol-insensitive CCK1R mutant Y140A was resistant to effects of both bile acids. These data suggest that bile acids compete with the action of cholesterol on CCK1R, probably by interacting at the same site, although the conformational impact of each bile acid appears to be different, with ursodeoxycholic acid capable of correcting the abnormal conformation of CCK1R in a high-cholesterol environment. This mechanism may contribute to the beneficial effect of ursodeoxycholic acid in reducing cholesterol gallstone formation.
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МЕЛЬНИКОВА, Е. Е., Н. В. БАРДУКОВ, М. С. ФОРНАРА та ін. "ВЛИЯНИЕ ГЕНОТИПОВ ПО IGF2, CCKAR И MC4R НА ФЕНОТИПИЧЕСКИЕ ПОКАЗАТЕЛИ И ПЛЕМЕННУЮ ЦЕННОСТЬ СВИНЕЙ ПО ХОЗЯЙСТВЕННО ПОЛЕЗНЫМ ПРИЗНАКАМ". Sel'skokhozyaistvennaya Biologiya 53, № 4 (2018): 723–34. http://dx.doi.org/10.15389/agrobiology.2018.4.723rus.
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Tinoco, A. B., A. I. Valenciano, M. Gómez-Boronat, et al. "Two cholecystokinin receptor subtypes are identified in goldfish, being the CCKAR involved in the regulation of intestinal motility." Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology 187 (September 2015): 193–201. http://dx.doi.org/10.1016/j.cbpa.2015.05.027.
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Dufresne, Marlène, Catherine Seva, and Daniel Fourmy. "Cholecystokinin and Gastrin Receptors." Physiological Reviews 86, no. 3 (2006): 805–47. http://dx.doi.org/10.1152/physrev.00014.2005.
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Cholecystokinin and gastrin receptors (CCK1R and CCK2R) are G protein-coupled receptors that have been the subject of intensive research in the last 10 years with corresponding advances in the understanding of their functioning and physiology. In this review, we first describe general properties of the receptors, such as the different signaling pathways used to exert short- and long-term effects and the structural data that explain their binding properties, activation, and regulation. We then focus on peripheral cholecystokinin receptors by describing their tissue distribution and physiological actions. Finally, pathophysiological peripheral actions of cholecystokinin receptors and their relevance in clinical disorders are reviewed.
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Hou, Ye, Mingyang Hu, Huanhuan Zhou, et al. "Neuronal Signal Transduction-Involved Genes in Pig Hypothalamus Affect Feed Efficiency as Revealed by Transcriptome Analysis." BioMed Research International 2018 (December 26, 2018): 1–10. http://dx.doi.org/10.1155/2018/5862571.
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Feed efficiency (FE) is an important trait affecting costs in swine industry. Investigation on FE-related genes in different tissues is valuable for molecular breeding. Hypothalamus is a convergent and integrated centre for multiple nutrient-related signals. The present study identified 363 differentially expressed (DE) genes and 14 DE lincRNAs in the hypothalamus of high- and low-FE Yorkshire pigs. Furthermore, 983 significantly correlated DE gene-lincRNA pairs were identified through weighted correlation network analysis (WGCNA) and Pearson correlation analysis. These DE genes were primarily enriched in the neuronal signal transduction process containing the upregulated genes of VIPR1, CCR1, CCR5, LEPR, INSR, ADRA1A, CCKAR, and ADORA3 and the downregulated genes of GRM1, GRM4, GRM5, and VIPR2, which were located in the cell membrane. These signal receptors were mainly connected to downstream Jak-STAT signaling that involved the increased genes (JAK2, STAT3, and POMC) and mTOR signaling pathway, including the decreased genes (CAMKK2, AMPK, and MTOR). STAT3 and AMPK genes also played a role in two major hypothalamic neurons of POMC and NPY/AGRP. A total of eight DE lincRNAs also participated in the potential network. In conclusion, neuronal signaling transduction-involved genes and lincRNAs were related to FE variation in pig hypothalamus.
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Melnikova, E. E., N. V. Bardukov, M. S. Fornara, et al. "EFFECTS OF GENOTYPES FOR IGF2, CCKAR AND MC4R ON THE PHENOTYPIC ESTIMATIONS AND BREEDING VALUES FOR PRODUCTIVE TRAITS IN PIGS." Sel'skokhozyaistvennaya Biologiya 53, no. 4 (2018): 723–34. http://dx.doi.org/10.15389/agrobiology.2018.4.723eng.
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Xu, Hong-Li, Ann W. Hsing, Emily Vogtmann, et al. "Variants in CCK and CCKAR genes to susceptibility to biliary tract cancers and stones: A population-based study in Shanghai, China." Journal of Gastroenterology and Hepatology 28, no. 9 (2013): 1476–81. http://dx.doi.org/10.1111/jgh.12278.
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Lieu, Pauline T., Thomas Machleidt, Bhaskar Thyagarajan, et al. "Generation of Site-Specific Retargeting Platform Cell Lines for Drug Discovery Using phiC31 and R4 Integrases." Journal of Biomolecular Screening 14, no. 10 (2009): 1207–15. http://dx.doi.org/10.1177/1087057109348941.
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One of the challenges in developing cell lines for high-throughput screening in drug discovery is the labor- and time-intensive process required to create stable clonal cell lines that express specific reporters or drug targets. The authors report here the generation of a site-specific retargeting platform in 3 different cell lines: adherent HEK293, suspension CHO-S, and a human embryonic cell line (BGO1V). These platform cell lines were generated by using a combination of 2 site-specific integrases to develop a system that allows one to efficiently target a gene of interest to a specific locus and generates rapid production of homogeneous cell pools that stably express the gene of interest. The phiC31 integrase was used to create a platform line by placing a target site for the R4 integrase into a pseudo attP site, and then the R4 integrase was used to place a gene of interest into specific R4 target site. The authors demonstrate the successful and rapid retargeting of a G-protein-coupled receptor (cholecystokinin receptor A, CCKAR), an ion channel (the transient receptor potential cation channel, subfamily M, member 8, TRPM8), and a GFP-c-Jun(1-79) fusion protein into the specific loci in these cell lines and show that these retargeted cell lines exhibit functional and pharmacological responses consistent with those reported in the literature.
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Nurgulsim, Kaster, Sayed Haidar Abbas Raza, Rajwali Khan, et al. "Identification of genetic variants the CCKAR gene and based on body measurement and carcass quality characteristics in Qinchuan beef cattle (Bos taurus)." Electronic Journal of Biotechnology 51 (May 2021): 1–7. http://dx.doi.org/10.1016/j.ejbt.2021.02.001.
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Obszynska, Jolanta A., Paul A. Atherfold, Manoj Nanji, et al. "Long-term proton pump induced hypergastrinaemia does induce lineage-specific restitution but not clonal expansion in benign Barrett's oesophagus in vivo." Gut 59, no. 2 (2009): 156–63. http://dx.doi.org/10.1136/gut.2009.186775.
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BackgroundBarrett's oesophagus is a common premalignant lesion caused partly by acid reflux. Although the requisite therapy, proton pump inhibitors (PPIs), have been implicated in the progression of Barrett's oesophagus in animal models, harmful effects of prolonged PPI therapy in Barrett's oesophagus is both inconclusive and controversial. We therefore aimed to test the role of PPI-induced hypergastrinaemia in vitro and see whether any biological parameters were useful surrogates of long-term therapy in man.MethodsWe undertook detailed serological and tissue assessment of gastrin and CCK2 receptors in 90 patients randomised to different doses of PPI therapy during a detailed 2-year follow-up. We also undertook a comprehensive study of cell models to study the consequential biological effects of gastrin on the mucosa.ResultsGastrin and its cognate receptor CCK2R were expressed highest in the stomach, then less in Barrett's oesophagus and least in squamous oesophagus (SqE) (n=20 paired t-test, p<0.01). Analysis of the change in Barrett's oesophagus segment length change in 70 patients who were randomised to high or low PPI dose showed no difference over 2 years (n=70 t-test, p=0.8). Prolonged PPI use did, however, increase the serum gastrin, (36 pg/ml±57 pg/ml to 103 pg/ml±94 pg/ml (paired t test, p<0.05)). In vitro gastrin also induced changes in OE33(E)cckr Barrett's oesophagus cells, but not OE21(E)cckr squamous cells, transfected with CCK2R; migration was induced by 1 ng/ml of gastrin but proliferation only increased with 100 ng/ml (paired t-test, p<0.01) and both were abolished by antagonists.ConclusionWhile the short-term effects of gastrin enhance epithelial restitution in Barrett's oesophagus (but not squamous mucosa) there is no clinical evidence that Barrett's oesophagus length expands over time. This study, which is the largest and longest term randomised controlled trial of gastrin biology in Barrett's oesophagus, is further proof of the clinical safety of PPI therapy.
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Tang, Wen Zhu, and Zong Jie Cui. "Permanent Photodynamic Activation of the Cholecystokinin 2 Receptor." Biomolecules 10, no. 2 (2020): 236. http://dx.doi.org/10.3390/biom10020236.
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The cholecystokinin 2 receptor (CCK2R) is expressed in the central nervous system and peripheral tissues, playing an important role in higher nervous and gastrointestinal functions, pain sensation, and cancer growth. CCK2R is reversibly activated by cholecystokinin or gastrin, but whether it can be activated permanently is not known. In this work, we found that CCK2R expressed ectopically in CHO-K1 cells was permanently activated in the dark by sulfonated aluminum phthalocyanine (SALPC/AlPcS4, 10–1000 nM), as monitored by Fura-2 fluorescent calcium imaging. Permanent CCK2R activation was also observed with AlPcS2, but not PcS4. CCK2R previously exposed to SALPC (3 and 10 nM) was sensitized by subsequent light irradiation (>580 nm, 31.5 mW·cm−2). After the genetically encoded protein photosensitizer mini singlet oxygen generator (miniSOG) was fused to the N-terminus of CCK2R and expressed in CHO-K1 cells, light irradiation (450 nm, 85 mW·cm−2) activated in-frame CCK2R (miniSOG-CCK2R), permanently triggering persistent calcium oscillations blocked by the CCK2R antagonist YM 022 (30 nM). From these data, it is concluded that SALPC is a long-lasting CCK2R agonist in the dark, and CCK2R is photogenetically activated permanently with miniSOG as photosensitizer. These properties of SALPC and CCK2R could be used to study CCK2R physiology and possibly for pain and cancer therapies.
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Whited, K. L., D. Thao, K. C. Kent Lloyd, A. S. Kopin, and H. E. Raybould. "Targeted disruption of the murine CCK1 receptor gene reduces intestinal lipid-induced feedback inhibition of gastric function." American Journal of Physiology-Gastrointestinal and Liver Physiology 291, no. 1 (2006): G156—G162. http://dx.doi.org/10.1152/ajpgi.00569.2005.
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Cholecystokinin (CCK), acting at CCK1 receptors (CCK1Rs) on intestinal vagal afferent terminals, has been implicated in the control of gastrointestinal function and food intake. Using CCK1R−/− mice, we tested the hypothesis that lipid-induced activation of the vagal afferent pathway and intestinal feedback of gastric function is CCK1R dependent. In anesthetized CCK1R+/+ (“wild type”) mice, meal-stimulated gastric acid secretion was inhibited by intestinal lipid infusion; this was abolished in CCK1R−/− mice. Gastric emptying of whole egg, measured by nuclear scintigraphy in awake mice, was significantly faster in CCK1R−/− than CCK1R+/+ mice. Gastric emptying of chow was significantly slowed in response to administration of CCK-8 (22 pmol) in CCK1R+/+ but not CCK1R−/− mice. Activation of the vagal afferent pathway was measured by immunohistochemical localization of Fos protein in the nucleus of the solitary tract (NTS; a region where vagal afferents terminate). CCK-8 (22 pmol ip) increased neuronal Fos expression in the NTS of fasted CCK1R+/+ mice; CCK-induced Fos expression was reduced by 97% in CCK1R−/− compared with CCK1R+/+ mice. Intralipid (0.2 ml of 20% Intralipid and 0.04 g lipid), but not saline, gavage increased Fos expression in the NTS of fasted CCK1R+/+ mice; lipid-induced Fos expression was decreased by 47% in CCK1R−/− compared with CCK1R+/+mice. We conclude that intestinal lipid activates the vagal afferent pathway, decreases gastric acid secretion, and delays gastric emptying via a CCK1R-dependent mechanism. Thus, despite a relatively normal phenotype, intestinal feedback in response to lipid is severely impaired in these mice.
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Blevins, James E., Daniel H. Moralejo, Tami H. Wolden-Hanson, et al. "Alterations in activity and energy expenditure contribute to lean phenotype in Fischer 344 rats lacking the cholecystokinin-1 receptor gene." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 303, no. 12 (2012): R1231—R1240. http://dx.doi.org/10.1152/ajpregu.00393.2012.
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CCK is hypothesized to inhibit meal size by acting at CCK1 receptors (CCK1R) on vagal afferent neurons that innervate the gastrointestinal tract and project to the hindbrain. Earlier studies have shown that obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which carry a spontaneous null mutation of the CCK1R, are hyperphagic and obese. Recent findings show that rats with CCK1R-null gene on a Fischer 344 background (Cck1r−/−) are lean and normophagic. In this study, the metabolic phenotype of this rat strain was further characterized. As expected, the CCK1R antagonist, devazepide, failed to stimulate food intake in the Cck1r−/− rats. Both Cck1r+/+ and Cck1r−/− rats became diet-induced obese (DIO) when maintained on a high-fat diet relative to chow-fed controls. Cck1r−/− rats consumed larger meals than controls during the dark cycle and smaller meals during the light cycle. These effects were accompanied by increased food intake, total spontaneous activity, and energy expenditure during the dark cycle and an apparent reduction in respiratory quotient during the light cycle. To assess whether enhanced responsiveness to anorexigenic factors may contribute to the lean phenotype, we examined the effects of melanotan II (MTII) on food intake and body weight. We found an enhanced effect of MTII in Cck1r−/− rats to suppress food intake and body weight following both central and peripheral administration. These results suggest that the lean phenotype is potentially driven by increases in total spontaneous activity and energy expenditure.
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Chen, Xu, and Barry Ganetzky. "A neuropeptide signaling pathway regulates synaptic growth in Drosophila." Journal of Cell Biology 196, no. 4 (2012): 529–43. http://dx.doi.org/10.1083/jcb.201109044.
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Neuropeptide signaling is integral to many aspects of neural communication, particularly modulation of membrane excitability and synaptic transmission. However, neuropeptides have not been clearly implicated in synaptic growth and development. Here, we demonstrate that cholecystokinin-like receptor (CCKLR) and drosulfakinin (DSK), its predicted ligand, are strong positive growth regulators of the Drosophila melanogaster larval neuromuscular junction (NMJ). Mutations of CCKLR or dsk produced severe NMJ undergrowth, whereas overexpression of CCKLR caused overgrowth. Presynaptic expression of CCKLR was necessary and sufficient for regulating NMJ growth. CCKLR and dsk mutants also reduced synaptic function in parallel with decreased NMJ size. Analysis of double mutants revealed that DSK/CCKLR regulation of NMJ growth occurs through the cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA)–cAMP response element binding protein (CREB) pathway. Our results demonstrate a novel role for neuropeptide signaling in synaptic development. Moreover, because the cAMP–PKA–CREB pathway is required for structural synaptic plasticity in learning and memory, DSK/CCKLR signaling may also contribute to these mechanisms.
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Qin, Yun, Stefan Imobersteg, Alain Blanc, et al. "Evaluation of Actinium-225 Labeled Minigastrin Analogue [225Ac]Ac-DOTA-PP-F11N for Targeted Alpha Particle Therapy." Pharmaceutics 12, no. 11 (2020): 1088. http://dx.doi.org/10.3390/pharmaceutics12111088.
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The overexpression of cholecystokinin B receptor (CCKBR) in human cancers led to the development of radiolabeled minigastrin analogues for targeted radionuclide therapy, which aims to deliver cytotoxic radiation specifically to cancer cells. Alpha emitters (e.g., actinium-225) possess high potency in cancer cell-killing and hold promise for the treatment of malignant tumors. In these preclinical studies, we developed and evaluated CCKBR-targeted alpha particle therapy. The cellular uptake and cytotoxic effect of actinium-225 labeled and HPLC-purified minigastrin analogue [225Ac]Ac-PP-F11N were characterized in the human squamous cancer A431 cells transfected with CCKBR. Nude mice bearing A431/CCKBR tumors were used for biodistribution and therapy studies followed by histological analysis and SPECT/CT imaging. In vitro, [225Ac]Ac-PP-F11N showed CCKBR-specific and efficient internalization rate and potent cytotoxicity. The biodistribution studies of [225Ac]Ac-PP-F11N revealed CCKBR-specific uptake in tumors, whereas the therapeutic studies demonstrated dose-dependent inhibition of tumor growth and extended mean survival time, without apparent toxicity. The histological analysis of kidney and stomach indicated no severe adverse effects after [225Ac]Ac-PP-F11N administration. The post-therapy SPECT-CT images with [111In]In-PP-F11N confirmed no CCKBR-positive tumor left in the mice with complete remission. In conclusion, our study demonstrates therapeutic efficacy of [225Ac]Ac-PP-F11N without acute radiotoxicity in CCKBR-positive cancer model.
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Angelastro, Peter S., Oleksii Sliusarenko, and Christine Jacobs-Wagner. "Polar Localization of the CckA Histidine Kinase and Cell Cycle Periodicity of the Essential Master Regulator CtrA in Caulobacter crescentus." Journal of Bacteriology 192, no. 2 (2009): 539–52. http://dx.doi.org/10.1128/jb.00985-09.
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ABSTRACT The phosphorylated form of the response regulator CtrA represses DNA replication initiation and regulates the transcription of about 100 cell cycle-regulated genes in Caulobacter crescentus. CtrA activity fluctuates during the cell cycle, and its periodicity is a key element of the engine that drives cell cycle progression. The histidine kinase CckA controls the phosphorylation not only of CtrA but also of CpdR, whose unphosphorylated form promotes CtrA proteolysis. Thus, CckA has a central role in establishing the cell cycle periodicity of CtrA activity by controlling both its phosphorylation and stability. Evidence suggests that the polar localization of CckA during the cell cycle plays a role in CckA function. However, the exact pattern of CckA localization remains controversial. Here, we describe a thorough, quantitative analysis of the spatiotemporal distribution of a functional and chromosomally produced CckA-monomeric green fluorescent protein fusion that affects current models of cell cycle regulation. We also identify two cis-acting regions in CckA that are important for its proper localization and function. The disruption of a PAS-like motif in the sensor domain affects the stability of CckA accumulation at the poles. This is accompanied by a partial loss in CckA function. Shortening an extended linker between β-sheets within the CckA catalysis-assisting ATP-binding domain has a more severe effect on CckA polar localization and function. This mutant strain exhibits a dramatic cell-to-cell variability in CpdR levels and CtrA cell cycle periodicity, suggesting that the cell cycle-coordinated polar localization of CckA may be important for the robustness of signal transduction and cell cycle progression.
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Santamarta, Irene, Antonio Rodríguez-García, Rosario Pérez-Redondo, Juan F. Martín, and Paloma Liras. "CcaR Is an Autoregulatory Protein That Binds to the ccaR and cefD-cmcI Promoters of the Cephamycin C-Clavulanic Acid Cluster in Streptomyces clavuligerus." Journal of Bacteriology 184, no. 11 (2002): 3106–13. http://dx.doi.org/10.1128/jb.184.11.3106-3113.2002.
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ABSTRACT The putative regulatory CcaR protein, which is encoded in the β-lactam supercluster of Streptomyces clavuligerus, has been partially purified by ammonium sulfate precipitation and heparin affinity chromatography. In addition, it was expressed in Escherichia coli, purified as a His-tagged recombinant protein (rCcaR), and used to raise anti-rCcaR antibodies. The partially purified CcaR protein from S. clavuligerus was able to bind DNA fragments containing the promoter regions of the ccaR gene itself and the bidirectional cefD-cmcI promoter region. In contrast, CcaR did not bind to DNA fragments with the promoter regions of other genes of the cephamycin-clavulanic acid supercluster including lat, blp, claR, car-cyp, and the unlinked argR gene. The DNA shifts obtained with CcaR were prevented by anti-rCcaR immunoglobulin G (IgG) antibodies but not by anti-rabbit IgG antibodies. ccaR and the bidirectional cefD-cmcI promoter region were fused to the xylE reporter gene and expressed in Streptomyces lividans and S. clavuligerus. These constructs produced low catechol dioxygenase activity in the absence of CcaR; activity was increased 1.7- to 4.6-fold in cultures expressing CcaR. Amplification of the ccaR promoter region lacking its coding sequence in a high-copy-number plasmid in S. clavuligerus ATCC 27064 resulted in a reduced production of cephamycin C and clavulanic acid, by 12 to 20% and 40 to 60%, respectively, due to titration of the CcaR regulator. These findings confirm that CcaR is a positively acting autoregulatory protein able to bind to its own promoter as well as to the cefD-cmcI bidirectional promoter region.
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Li, Yuan, and Zong Jie Cui. "NanoLuc Bioluminescence-Driven Photodynamic Activation of Cholecystokinin 1 Receptor with Genetically-Encoded Protein Photosensitizer MiniSOG." International Journal of Molecular Sciences 21, no. 11 (2020): 3763. http://dx.doi.org/10.3390/ijms21113763.
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In contrast to reversible activation by agonist, cholecystokinin 1 receptor (CCK1R) is permanently activated by singlet oxygen generated in photodynamic action, with sulphonated aluminium phthalocyanine or genetically encoded mini singlet oxygen generator (miniSOG) as photosensitizer. In these works, a halogen light source was used to power photodynamic action. For possible in vivo application of photodynamic CCK1R physiology, bearing a cumbersome light-delivery device connected to an external light source by experimental animals might interfere with their behavior. Therefore, in the present work, the possibility of bioluminescence-driven miniSOG photodynamic CCK1R activation was examined, as monitored by Fura-2 calcium imaging. In parallel experiments, it was found that, after plasma membrane (PM)-localized expression of miniSOGPM in AR4-2J cells, light irradiation with blue light-emitting diode (LED) (450 nm, 85 mW·cm−2, 1.5 min) induced persistent calcium oscillations that were blocked by CCK1R antagonist devazepide 2 nM. NanoLuc was expressed bicistronically with miniSOGPM via an internal ribosome entry site (IRES) sequence (pminiSOGPM-IRES-NanoLuc). The resultant miniSOGPM-IRES-NanoLuc-AR4-2J cells were found to generate strong bioluminescence upon addition of NanoLuc substrate coelenterazine. Strikingly, coelenterazine 5 microM was found to trigger long-lasting calcium oscillations (a hallmark for permanent CCK1R activation) in perifused miniSOGPM-IRES-NanoLuc-AR4-2J cells. These data indicate that NanoLuc bioluminescence can drive miniSOGPM photodynamic CCK1R activation, laying the foundation for its future in vivo applications.
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Li, Yuan, and Zong Jie Cui. "Photodynamic Activation of Cholecystokinin 1 Receptor with Different Genetically Encoded Protein Photosensitizers and from Varied Subcellular Sites." Biomolecules 10, no. 10 (2020): 1423. http://dx.doi.org/10.3390/biom10101423.
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Cholecystokinin 1 receptor (CCK1R) is activated by singlet oxygen (1O2) generated in photodynamic action with sulphonated aluminum phthalocyanine (SALPC) or genetically encoded protein photosensitizer (GEPP) KillerRed or mini singlet oxygen generator (miniSOG). A large number of GEPP with varied 1O2 quantum yields have appeared recently; therefore, in the present work, the efficacy of different GEPP to photodynamically activate CCK1R was examined, as monitored by Fura-2 calcium imaging. KillerRed, miniSOG, miniSOG2, singlet oxygen protein photosensitizer (SOPP), flavin-binding fluorescent protein from Methylobacterium radiotolerans with point mutation C71G (Mr4511C71G), and flavin-binding fluorescent protein from Dinoroseobacter shibae (DsFbFP) were expressed at the plasma membrane (PM) in AR4-2J cells, which express endogenous CCK1R. Light irradiation (KillerRed: white light 85.3 mW‧cm−2, 4’ and all others: LED 450 nm, 85 mW·cm−2, 1.5′) of GEPPPM-expressing AR4-2J was found to all trigger persistent calcium oscillations, a hallmark of permanent photodynamic CCK1R activation; DsFbFP was the least effective, due to poor expression. miniSOG was targeted to PM, mitochondria (MT) or lysosomes (LS) in AR4-2J in parallel experiments; LED light irradiation was found to all induce persistent calcium oscillations. In miniSOGPM-AR4-2J cells, light emitting diode (LED) light irradiation-induced calcium oscillations were readily inhibited by CCK1R antagonist devazepide 2 nM; miniSOGMT-AR4-2J cells were less susceptible, but miniSOGLS-AR4-2J cells were not inhibited. In conclusion, different GEPPPM could all photodynamically activate CCK1R. Intracellular GEPP photodynamic action may prove particularly suited to study intracellular GPCR.
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Mann, Thomas H., and Lucy Shapiro. "Integration of cell cycle signals by multi-PAS domain kinases." Proceedings of the National Academy of Sciences 115, no. 30 (2018): E7166—E7173. http://dx.doi.org/10.1073/pnas.1808543115.
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Spatial control of intracellular signaling relies on signaling proteins sensing their subcellular environment. In many cases, a large number of upstream signals are funneled to a master regulator of cellular behavior, but it remains unclear how individual proteins can rapidly integrate a complex array of signals within the appropriate spatial niche within the cell. As a model for how subcellular spatial information can control signaling activity, we have reconstituted the cell pole-specific control of the master regulator kinase/phosphatase CckA from the asymmetrically dividing bacterium Caulobacter crescentus. CckA is active as a kinase only when it accumulates within a microdomain at the new cell pole, where it colocalizes with the pseudokinase DivL. Both proteins contain multiple PAS domains, a multifunctional class of sensory domains present across the kingdoms of life. Here, we show that CckA uses its PAS domains to integrate information from DivL and its own oligomerization state to control the balance of its kinase and phosphatase activities. We reconstituted the DivL–CckA complex on liposomes in vitro and found that DivL directly controls the CckA kinase/phosphatase switch, and that stimulation of either CckA catalytic activity depends on the second of its two PAS domains. We further show that CckA oligomerizes through a multidomain interaction that is critical for stimulation of kinase activity by DivL, while DivL stimulation of CckA phosphatase activity is independent of CckA homooligomerization. Our results broadly demonstrate how signaling factors can leverage information from their subcellular niche to drive spatiotemporal control of cell signaling.
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Grob, Nathalie M., Roger Schibli, Martin Béhé, and Thomas L. Mindt. "Improved Tumor-Targeting with Peptidomimetic Analogs of Minigastrin 177Lu-PP-F11N." Cancers 13, no. 11 (2021): 2629. http://dx.doi.org/10.3390/cancers13112629.
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The cholecystokinin-2 receptor (CCK2R) is an attractive target in nuclear medicine due to its overexpression by different tumors. Several radiolabeled peptidic ligands targeting the CCK2R have been investigated in the past; however, their low stability against proteases can limit their uptake in tumors and metastases. Substitution of single or multiple amide bonds with metabolically stable 1,4-disubstituted 1,2,3-triazoles as amide bond bioisosteres proved a promising strategy for improving the tumor-targeting properties of a truncated analog of minigastrin. In this study, we applied the previously studied structural modifications to improve the pharmacokinetic and pharmacodynamic properties of PP-F11N, a minigastrin analog currently in clinical trials. Novel minigastrins (NMGs) as analogs of PP-F11N with one or two amide bonds substituted by 1,2,3-triazoles were synthesized, radiolabeled with 177Lu3+, and subjected to full evaluation in vitro (cell internalization, receptor affinity, stability in blood plasma) and in vivo (stability, biodistribution, SPECT/CT imaging). NMGs with triazoles inserted between the amino acids DGlu10-Ala11 and/or Tyr12-Gly13 showed a significantly increased cellular uptake and affinity toward the CCK2R in vitro. Resistance against the metabolic degradation of the NMGs was comparable to those of the clinical candidate PP-F11N. Imaging by SPECT/CT and biodistribution studies demonstrated a higher uptake in CCK2R-positive tumors but also in the CCK2R-positive stomach. The peptidomimetic compounds showed a slow tumor washout and high tumor-to-kidney ratios. The structural modifications led to the identification of analogs with promising properties for progression to clinical applications in the diagnosis and therapy of CCK2R-positive neoplasms.
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Klingler, Maximilian, Anton Amadeus Hörmann, and Elisabeth Von Guggenberg. "Cholecystokinin-2 Receptor Targeting with Radiolabeled Peptides: Current Status and Future Directions." Current Medicinal Chemistry 27, no. 41 (2020): 7112–32. http://dx.doi.org/10.2174/0929867327666200625143035.
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A wide variety of radiolabeled peptide analogs for specific targeting of cholecystokinin- 2 receptors (CCK2R) has been developed in the last decades. Peptide probes based on the natural ligands Minigastrin (MG) and Cholecystokinin (CCK) have a high potential for molecular imaging and targeted radiotherapy of different human tumors, such as Medullary Thyroid Carcinoma (MTC) and Small Cell Lung Cancer (SCLC). MG analogs with high persistent uptake in CCK2R expressing tumors have been preferably used for the development of radiolabeled peptide analogs. The clinical translation of CCK2R targeting has been prevented due to high kidney uptake or low metabolic stability of the different radiopeptides developed. Great efforts in radiopharmaceutical development have been undertaken to overcome these limitations. Various modifications in the linear peptide sequence of MG have been introduced mainly with the aim to reduce kidney retention. Furthermore, improved tumor uptake could be obtained by in situ stabilization of the radiopeptide against enzymatic degradation through coinjection of peptidase inhibitors. Recent developments focusing on the stabilization of the Cterminal receptor binding sequence (Trp-Met-Asp-Phe-NH2) have led to new radiolabeled MG analogs with highly improved tumor uptake and tumor-to-kidney ratio. In this review, all the different aspects in the radiopharmaceutical development of CCK2R targeting peptide probes are covered, giving also an overview on the clinical investigations performed so far. The recent development of radiolabeled MG analogs, which are highly stabilized against enzymatic degradation in vivo, promises to have a high impact on the clinical management of patients with CCK2R expressing tumors in the near future.
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Klingler, Maximilian, Christine Rangger, Dominik Summer, Piriya Kaeopookum, Clemens Decristoforo, and Elisabeth von Guggenberg. "Cholecystokinin-2 Receptor Targeting with Novel C-terminally Stabilized HYNIC-Minigastrin Analogs Radiolabeled with Technetium-99m." Pharmaceuticals 12, no. 1 (2019): 13. http://dx.doi.org/10.3390/ph12010013.
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The high overexpression of cholecystokinin-2 receptors (CCK2R) in tumors, such as medullary thyroid carcinoma, allows for highly specific diagnostic and therapeutic targeting with radiolabeled peptide probes derived from natural ligands for the receptor. Based on the ideal imaging characteristics, high availability and low cost of technetium-99m (99mTc)-labeled radiopharmaceuticals we have developed two hydrazinonicotinic acid (HYNIC) conjugated minigastrin analogs allowing labeling at high specific activity. The CCK2R targeting peptide conjugates show specific amino acid substitutions in the C-terminal receptor-specific sequence with the aim to increase stability and tumor targeting. The CCK2R affinity and the cell uptake of the new radioligands were analyzed using A431 human epidermoid carcinoma cells stably transfected with human CCK2R and mock transfected cells. Metabolic studies in BALB/c mice revealed a high resistance against enzymatic degradation for both radioligands. Biodistribution studies in tumor-xenografted athymic BALB/c nude mice at 1 h and 4 h p.i. showed that the two 99mTc-labeled compounds showed varying uptake in receptor expressing organs, stomach and pancreas (1.3–10.4% IA/g), as well as kidneys, the main route of excretion (7.8–19.9% IA/g). The tumor uptake in A431-CCK2R xenografts was 24.75 ± 4.38% IA/g for [99mTc]Tc-HYNIC-MGS5 and 42.48 ± 6.99% IA/g for [99mTc]Tc-HYNIC-MGS11 at 4 h p.i., whereas the tumor-to-kidney ratio was comparable (2.6–3.3). On demand availability and potential application for radioguided surgery of a 99mTc-labeled minigastrin analog support the further evaluation of these highly promising new compounds.
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Iniesta, Antonio A., Nathan J. Hillson, and Lucy Shapiro. "Polar Remodeling and Histidine Kinase Activation, Which Is Essential for Caulobacter Cell Cycle Progression, Are Dependent on DNA Replication Initiation." Journal of Bacteriology 192, no. 15 (2010): 3893–902. http://dx.doi.org/10.1128/jb.00468-10.
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ABSTRACT Caulobacter crescentus initiates a single round of DNA replication during each cell cycle. Following the initiation of DNA replication, the essential CckA histidine kinase is activated by phosphorylation, which (via the ChpT phosphotransferase) enables the phosphorylation and activation of the CtrA global regulator. CtrA∼P then blocks the reinitiation of replication while regulating the transcription of a large number of cell cycle-controlled genes. It has been shown that DNA replication serves as a checkpoint for flagellar biosynthesis and cell division and that this checkpoint is mediated by the availability of active CtrA. Because CckA∼P promotes the activation of CtrA, we addressed the question of what controls the temporal activation of CckA. We found that the initiation of DNA replication is a prerequisite for remodeling the new cell pole, which includes the localization of the DivL protein kinase to that pole and, consequently, the localization, autophosphorylation, and activation of CckA at that pole. Thus, CckA activation is dependent on polar remodeling and a DNA replication initiation checkpoint that is tightly integrated with the polar phospho-signaling cascade governing cell cycle progression.
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Summer, Dominik, Christine Rangger, Maximilian Klingler, et al. "Exploiting the Concept of Multivalency with 68Ga- and 89Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression." Contrast Media & Molecular Imaging 2018 (2018): 1–12. http://dx.doi.org/10.1155/2018/3171794.
Full textAbstract:
Cholecystokinin-2 receptors (CCK2R) are overexpressed in a variety of malignant diseases and therefore have gained certain attention for peptide receptor radionuclide imaging. Among extensive approaches to improve pharmacokinetics and metabolic stability of minigastrin (MG) based radioligands, the concept of multivalency for enhanced tumour targeting has not been investigated extensively. We therefore utilized fusarinine C (FSC) as chelating scaffold for novel mono-, di-, and trimeric bioconjugates for targeting CCK2R expression. FSC-based imaging probes were radiolabelled with positron emitting radionuclides (gallium-68 and zirconium-89) and characterized in vitro (logD, IC50, and cell uptake) and in vivo (metabolic stability in BALB/c mice, biodistribution profile, and microPET/CT imaging in A431-CCK2R/A431-mock tumour xenografted BALB/c nude mice). Improved targeting did not fully correlate with the grade of multimerization. The divalent probe showed higher receptor affinity and increased CCK2R mediated cell uptake while the trimer remained comparable to the monomer. In vivo biodistribution studies 1 h after administration of the 68Ga-labelled radioligands confirmed this trend, but imaging at late time point (24 h) with 89Zr-labelled counterparts showed a clearly enhanced imaging contrast of the trimeric probe compared to the mono- and dimer. Furthermore, in vivo stability studies showed a higher metabolic stability for multimeric probes compared to the monomeric bioconjugate. In summary, we could show that FSC can be utilized as suitable scaffold for novel mono- and multivalent imaging probes for CCK2R-related malignancies with partly improved targeting properties for multivalent conjugates. The increased tumour accumulation of the trimer 24 h postinjection (p.i.) can be explained by slower clearance and increased metabolic stability of multimeric conjugates.
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Gu, Daqian, Dandong Fang, Mingming Zhang та ін. "Gastrin, via activation of PPARα, protects the kidney against hypertensive injury". Clinical Science 135, № 2 (2021): 409–27. http://dx.doi.org/10.1042/cs20201340.
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Abstract Hypertensive nephropathy (HN) is a common cause of end-stage renal disease with renal fibrosis; chronic kidney disease is associated with elevated serum gastrin. However, the relationship between gastrin and renal fibrosis in HN is still unknown. We, now, report that mice with angiotensin II (Ang II)-induced HN had increased renal cholecystokinin receptor B (CCKBR) expression. Knockout of CCKBR in mice aggravated, while long-term subcutaneous infusion of gastrin ameliorated the renal injury and interstitial fibrosis in HN and unilateral ureteral obstruction (UUO). The protective effects of gastrin on renal fibrosis can be independent of its regulation of blood pressure, because in UUO, gastrin decreased renal fibrosis without affecting blood pressure. Gastrin treatment decreased Ang II-induced renal tubule cell apoptosis, reversed Ang II-mediated inhibition of macrophage efferocytosis, and reduced renal inflammation. A screening of the regulatory factors of efferocytosis showed involvement of peroxisome proliferator-activated receptor α (PPAR-α). Knockdown of PPAR-α by shRNA blocked the anti-fibrotic effect of gastrin in vitro in mouse renal proximal tubule cells and macrophages. Immunofluorescence microscopy, Western blotting, luciferase reporter, and Cut&tag-qPCR analyses showed that CCKBR may be a transcription factor of PPAR-α, because gastrin treatment induced CCKBR translocation from cytosol to nucleus, binding to the PPAR-α promoter region, and increasing PPAR-α gene transcription. In conclusion, gastrin protects against HN by normalizing blood pressure, decreasing renal tubule cell apoptosis, and increasing macrophage efferocytosis. Gastrin-mediated CCKBR nuclear translocation may make it act as a transcription factor of PPAR-α, which is a novel signaling pathway. Gastrin may be a new potential drug for HN therapy.
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Liu, Fang, Yuanzhen Cao, Kevin Pinz, et al. "First-in-Human CLL1-CD33 Compound CAR T Cell Therapy Induces Complete Remission in Patients with Refractory Acute Myeloid Leukemia: Update on Phase 1 Clinical Trial." Blood 132, Supplement 1 (2018): 901. http://dx.doi.org/10.1182/blood-2018-99-110579.
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Abstract Background CD19-specific chimeric antigen receptor (CAR) T cell therapy has achieved high efficacy in acute lymphoblastic leukemia patients. However, the treatment of acute myeloid leukemia (AML) has remained a particular challenge due to the heterogeneity of AML bearing cells, which renders single antigen targeting CAR T cell therapy ineffective. CLL1 and CD33 are often used as targets for AML CAR T cell therapy. CLL1 is associated with leukemia stem cells and disease relapse, and CD33 is expressed on the bulk AML disease. Previously, we demonstrated the profound anti-tumor activity of CLL1-CD33 compound CAR (cCAR) T cells. Here we present the efficacy of cCAR in preclinical study and update the success in level 1 dose escalation clinical trial on relapsed/refractory AML patients. Methods We engineered a cCAR comprising of an anti-CLL1 CAR linked to an anti- CD33 CAR via a self-cleaving P2A peptide and expressing both functional CAR molecules on the surface of a T-cell cell. We tested the anti-leukemic activities of CLL1-CD33 cCAR using multiple AML cell lines, primary human AML samples, human leukemia cell line (REH cells) expressing either CLL1 or CD33, and multiple mouse models. An alemtuzumab safety switch has also been established to ensure the elimination of CAR T cells following tumor eradication. Children and adults with relapsed/refractory AML were enrolled in our phase 1 dose escalation trial with primary objective to evaluate the safety of cCAR and secondary objective to assess the efficacy of cCAR anti-tumor activity. Results Co-culture assays results showed that cCAR displayed profound tumor killing effects in AML cell lines, primary patient samples and multiple mouse model systems. Our preclinical findings suggest that cCAR, targeting two discrete AML antigens: CLL1 and CD33, is an effective two-pronged approach in treating bulk AML disease and eradicating leukemia stem cells. Patients enrolled in the phase 1 dose escalation trial have shown remarkable response to cCAR treatment. Noticeably, a 6-yr-old female patient diagnosed with a complex karyotype AML including FLT3-ITD mutation had achieved complete remission. The patient was diagnosed with Fanconi anemia, which had progressed to juvenile myelomonocytic leukemia and eventually transformed into AML. The patient had been resistant to multiple lines of treatments, including 5 cycles of chemotherapy with FLT3 inhibitor prior to receiving cCAR. Before the treatment, patient's leukemia blasts comprised 73% of the peripheral blood mononuclear cells and 81% of the bone marrow. Patient underwent lymphodepletion therapy (Fludarabine and Cyclophosphamide) prior to cCAR infusion. Two split doses, each consisting of 1x106/kg CAR T cells, were infused on day 1 and day 2 respectively. On day 12, while leukemia blast still counting up to 98% of the bone marrow (Fig. 1A), robust CAR T cell expansion was detected in both peripheral blood and bone marrow. On day 19, patient achieved MRD- complete remission with bone marrow aspirates revealing complete ablation of myeloid cells (Fig. 1B). Flow cytometry confirmed the absence of leukemia blasts and showed that CAR T cells comprised 36% of the PBMC and 60% of the bone marrow. The patient later underwent non-myeloablative hematopoietic cell transplantation with less toxicities compared to conventional total body radiation and high dose chemotherapies. Updated results on other patients enrolled in this clinical trial including adverse events will be presented. Conclusion Our first-in-human clinical trial demonstrates promising efficacy of cCAR therapy in treating patients with relapsed/ refractory AML. cCAR is able to eradicate leukemia blasts and leukemia stem cells, exerting a profound tumor killing effect that is superior to single target CAR T cell therapies. cCAR is also shown to induce total myeloid ablation in bone marrow, suggesting that it may act as a safer alternative to avoid the severe toxicities caused by standard bone marrow ablation regimens without sacrificing the anti-tumor efficacy. This strategy will likely benefit patients who are unable to tolerate total body radiation or high dose chemotherapies. In addition to AML, cCAR also has the potential to treat blast crisis developed from myelodysplastic syndrome, chronic myeloid leukemia, and chronic myeloproliferative neoplasm. Disclosures Pinz: iCell Gene Therapeutics LLC: Employment. Ma:iCAR Bio Therapeutics Ltd: Employment. Wada:iCell Gene Therapeutics LLC: Employment. Chen:iCell Gene Therapeutics LLC: Employment. Ma:iCell Gene Therapeutics LLC: Employment. Ma:iCell Gene Therapeutics LLC, iCAR Bio Therapeutics Ltd: Consultancy, Equity Ownership, Research Funding.